Common diseases, such as heart disease, diabetes, and cancer, exhibit multifactorial etiologies with clear genetic and environmental contributions. Tremendous progress in understanding the genetic basis of common disease has been made during the past decade through the sequencing of the human and other genomes, analysis of common variation in human populations, and the development of high throughput technologies for genotyping and gene expression analyses. Over the past several years, Human Genome Wide Association Studies (GWAS) have robustly revealed hundreds of novel loci for common diseases, although in most cases these explain a small fraction of the estimated genetic component. Efforts to extend association approaches, by searching for less common or rare variants using array technologies and high throughput sequencing, are underway. It has also become clear that epigenetics, of which DNA methylation is one of the more stable and heritable manifestations, is an important, although largely uncharacterized, contributor to common diseases. We now propose to extend GWAS in a novel direction by examining, on a global level, the relationship between the methylation state of the genome, DNA variation, gene expression, and physiologic traits associated with common disease. The proposal evolved from the complementary ongoing studies in the laboratories of Drs. Lusis, Pellegrini, and Jacobsen, which coincide with the development of highly efficient sequencing technologies that have made large scale bisulfite sequencing studies feasible. Specifically, the laboratory of Dr. Lusis has developed a systems genetics resource consisting of 100 inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP), that has sufficient power to achieve high resolution mapping (1-2 Mb) for loci contributing to transcriptomic, proteomic, metabolomic, and physiologic traits. The laboratories of Drs. Pellegrini and Jacobsen have the capacity to contribute the latest generation sequencing technology and expertise for the purpose of establishing the genome-wide DNA methylation status for 100 mouse strains in the HMDP at single base resolution. This study will represent the first systematic effort to associate epigenetic patterns with metabolic and common disease phenotypes on a genome-wide scale. If funded, we believe this project will significantly alter the paradigm of GWAS studies, by demonstrating the impact of epigenetics on heritable phenotypic traits.